Regulation of Hormone Resistant Breast Cancer by IGF and Insulin System Signaling Both effective and tolerable, hormonal agents such as tamoxifen and aromatase inhibitors have had a profound Impact on the treatment of estrogen receptor positive (ER^) breast cancer in the adjuvant and metastatic setting. ER+ breast cancers represent the majority of all breast cancer. However, both primary and acquired resistance to these agents is common and developing new methods to overcome or prevent resistance would have a major impact in breast cancer. Insulin-like growth factor (IGF) signaling has been implicated as a major resistance pathway to therapies directed at the ER through the activation of two membrane receptor tyrosine kinases: 1) IGF-I receptor (IGF-IR) through binding in IGF-I and IGF-II and the 2) InsR Isoform A (InsR-A) through binding of IGF-II. We now demonstrate evidence that complete blockade of both IGF signaling receptors with a tyrosine kinase inhibitor (BMS-754807) is sufficient to reverse resistance to hormonal therapy in vivo. In contrast, IGF-IR inhibition alone did not induce regression and led to upregulation of InsR-A Isoforms. It is unclear if the metabolic isoform of the InsR (InsR-B), which binds Ins, but not IGF-I or IGF-II is important to proliferation and survival signaling in hormonal therapy resistance. This question is important, as BMS-754807 inhibits both InsR isoforms in addition to IGF-IR and may have potential metabolic liabilities of blocking the action of Ins on InsR-B. However, it is also plausible that Ins signaling blockade is important to reversal of hormone therapy resistance. Our overarching goal is to determine which IGF/Ins signaling components are necessary for this effect. We hypothesize that IGF blockade is sufficient to overcome hormonal therapy resistance in vivo in multiple models, has less potential to upregulate alternative signaling mechanisms and will be tolerable at effective doses in breast cancer patients. To test these hypotheses, we propose to: 1) optimize BMS-754807 combinations in hormonal therapy resistant models, 2) determine if Ins and/or InsR-A signaling is sufficient for IGF-IR-independent resistance to homrional therapy and 3) evaluate the efficacy of BMS-754807 and letrozole and perform correlative studies in patients with breast cancer.